Significance G protein-coupled receptors (GPCRs) regulate a wide variety of important cellular processes and are targeted by a large fraction of approved drugs. GPCRs signal by activating heterotrimeric G proteins and must couple to a select subset of G proteins to produce appropriate intracellular responses. It is not known how GPCRs select G proteins, but it is generally accepted that the Gα subunit C terminus is the primary G protein determinant of coupling selectivity. We systematically studied coupling of GPCRs to four families of G proteins and chimeras with C terminal regions that were exchanged between families. We uncovered rules for coupling selectivity and found that different GPCRs can recognize different features of the same G protein for selective coupling.